Lung infections caused by antibiotic-resistant bacteria are a constant threat for people with cystic fibrosis. Now researchers have identified a new mechanism by which bacteria hide from antibiotics in the respiratory tract. Consequently, treatment strategies need to consider this, including when developing new drugs.
Most people with cystic fibrosis have Pseudomonas aeruginosa infections in their lungs. Cystic fibrosis causes people to produce very thick mucus in the lungs that is a haven for bacteria.
Antibiotics are sometimes unable to combat certain bacterial infections, which can become chronic and lead to antibiotic resistance and a steep decline in health.
New research shows that P. aeruginosa can develop resistance in a novel way. This special resistance mechanism may explain why some types of antibiotics do not succeed in combatting infections with P. aeruginosa even though it appears to be sensitive in the usual laboratory tests carried out in hospitals. Understanding the mechanism may also lead to alternative treatments.
“This discovery opens up the possibility of targeting people with cystic fibrosis for antibiotic treatment for P. aeruginosa and developing new types of treatment that target them more effectively,” explains a researcher behind the study, Pablo Laborda Martínez, Postdoctoral Fellow, Rigshospitalet, Copenhagen and Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
The research has been published in Nature Communications.
Mutation involved in antibiotic resistance
The researchers investigated a special gene called mexZ in P. aeruginosa that is often mutated in bacteria infecting people with cystic fibrosis treated with antibiotics.
The mexZ gene encodes a protein that regulates an efflux pump, which helps P. aeruginosa to eject antibiotics from the cell. The protein is specifically involved in regulating the activity of the so-called MexXY efflux pump, but mutations in mexZ disrupt its function.
The research group’s results have shown that 40% of young people with cystic fibrosis have airway infections with strains of P. aeruginosa harbouring mexZ mutations which probably have a very significant role in the ability of P. aeruginosa to adapt to the environment of the infection.
“Our previous studies have also shown that mexZ mutations do not lead to higher levels of antibiotic resistance in standard laboratory tests, and that was a big surprise. We therefore set out to investigate the functions of the genes and how they affect the ability of P. aeruginosa to thrive during infection,” says Pablo Laborda Martínez.
Studying bacterial infections in cell layers
The researchers thoroughly investigated what happens to mexZ-mutated bacteria by using various miniature human airway infection models of the lung epithelial layer similar to what is in the lungs of people with cystic fibrosis or healthy people.
They then enabled both mutated and wild-type P. aeruginosa to infect the epithelial layers and observed what happened.
Unexpected resistance mechanism
The results were quite surprising.
In the various infection models, the researchers found that wild-type P. aeruginosa infects the lung tissue by forming colonies in the apical side of the epithelium: the outer cell layer facing the lungs.
However, mexZ-mutated bacteria infected the intraepithelial compartment between the cells in the lung tissue.
The mutated bacteria in the intraepithelial layer were much better protected against antibiotics because their location in the cell layer is not easily accessed by antibiotics – which the researchers discovered when they tried to combat the infections with three types of antibiotics.
“This gives us new understanding of how P. aeruginosa can become antibiotic-resistant among people with cystic fibrosis. The bacteria do not become better at surviving the direct action of antibiotics but are hidden from the antibiotics,” explains Pablo Laborda Martínez.
Leading to new treatments
According to Pablo Laborda Martínez, the new discovery has great perspectives. Doctors treating people with cystic fibrosis could analyse possible mexZ mutations in P. aeruginosa to guide treatment.
People infected with mexZ-mutated P. aeruginosa may need to switch to antibiotics that are better able to penetrate the intraepithelial compartment between the cells in which the mexZ-mutated P. aeruginosa are located.
Another possibility is to develop entirely new types of treatment that specifically target mexZ-mutated P. aeruginosa.
Mutations in mexZ do more than just regulate the efflux pump. The mutations also cause P. aeruginosa to produce more LecA lectin, which the cells require to anchor themselves to the intraepithelial layers and avoid the antibiotics.
“Now that we know about this phenomenon and know that LecA is involved, we may be able to develop treatments that counteract this so that the P. aeruginosa will continue to be susceptible to antibiotics. In addition, these observations and treatment options are not just relevant to people with cystic fibrosis but may also benefit other people with persistent P. aeruginosa infections, such as people with other severe lung diseases or with a high risk of lung infections because of a compromised immune system or a history of smoking,” concludes Pablo Laborda Martínez.
